The present invention provides therapeutic formulations for solutions of Δ9-tetrahydrocannabinol (Δ9 THC) to be delivered by metered dose inhalers. The formulations, which use, non-CFC propellants, provide a stable aerosol-deliverable source of Δ9 THC for the treatment of various medical conditions, such as: nausea and vomiting associated with chemotherapy-muscle spasticity; pain; anorexia associated with AIDS wasting syndrome, epilepsy; glaucoma; bronchial asthma; and mood disorders.

Imágenes(8)

Reclamaciones(16)

We claim:

1. A method of administering a pharmaceutically effective dose of aerosolized Δ9 tetrahydrocannabinol to a patient, comprising the steps of:

providing a solution comprising a pharmaceutically acceptable form of Δ9 tetrahydrocannabinol (THC) in a hydrofluoroalkane, said solution having not more than 15% w/w of a pharmaceutically acceptable solvent;

aerosolizing the THC solution to provide respirable droplets comprising THC wherein at least 20% of the mass of the respirable droplets comprise droplets having an aerodynamic diameter of less than 5.8 μm;

administering a pharmaceutically effective does of said respirable droplets to a patient's lungs.

2. A method of administering a pharmaceutically effective dose of aerosolized Δ9 tetrahydrocannabinol to a patient, comprising the steps of:

providing a solution comprising a pharmaceutically acceptable form of tetrahydrocannabinol (THC) in a hydrofluoroalkane, said solution having not more than 15% w/w of a pharmaceutically acceptable solvent;

aerosolizing the solution to provide respirable droplets comprising THC wherein at least 20% of the mass of the respirable droplets comprise droplets having an aerodynamic diameter of less than 5.8 μm;

administering a pharmaceutically effective dose of said respirable droplets to a patient's lungs to achieve brain levels of THC that are substantially the same as blood levels of THC in said patient.

3. The method of claim 2 wherein said solution comprises less than 15% w/w of a solvent selected from the group consisting of ethanol, propanol, propylene glycol, glycerol, and polyethylene glycol.

4. The method of claim 3 wherein said solvent comprises ethanol.

5. The method of claim 1 wherein said solution consists essentially of a hydrofluoroalkane propellant and Δ9-tetrahydrocannabinol.

6. The method of claim 1 wherein said pharmaceutically effective dose is sufficient to reduce nausea.

7. The method of claim 1 wherein said pharmaceutically effective dose is sufficient to reduce vomiting.

8. The method of claim 1 wherein said pharmaceutically effective dose is sufficient to reduce pain.

12. The method of claim 1 wherein said pharmaceutically effective dose is sufficient to increase appetite in patients suffering from cachexia.

13. The method of claim 2 wherein said pharmaceutically acceptable form of THC is pure Δ9-tetrahydrocannabinol and said hydrocannabinol is selected from the group consisting of hydrofluoroalkane (HFA) 134a and HFA 227.

14. The method of claim 2 wherein the droplets are less than about 10 μm.

15. A method according to claim 1 wherein the pharmaceutically effective dose is effective to achieve a serum concentration level in a patient of 10-100 ng/ml fifteen minutes following inhalation.

16. A method according to claim 1 comprising a pharmaceutically acceptable salt of Δ9-tetrahydrocannabinol.

Descripción

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 09/273,766 filed Mar. 22, 1999, now U.S. Pat. No. 6,509,005 which claims priority of U.S. provisional application Ser. No. 60/105,850 filed October 27, 1998, and the complete contents of those applications are incorporated herein by reference.

Funding for the research which led to this invention was provided in part by the United States Government in grant #DA 02396 and DA-07027 from the National Institutes of Health and the government may have certain rights in this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is generally related to the therapeutic use of Δ9 Tetrahydrocannabinol (Δ9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of Δ9 THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood disorders, and the like.

The year after the 1997 NIH study, the House of Lords made a recommendation to the British government (House-of-Lords-Select-Committee-on-Science-and-Technology, 1998) to reschedule marijuana. Similarly, there have been efforts to decriminalize marijuana in the United States.

When marijuana is used as a recreational psychoactive drug, the active ingredient Δ9 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized Δ9 THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. The pharmacokinetics of the administration of Δ9 THC is described in PDR Physician's Desk Reference (49) Montvalek, New Jersey: Medical Economics Data Production Co. (1995), pp.2787; Ohlsson, A., Lindgren J. E., Wahlen, A., Agurall, S., Hollister, L. E. and Gillespie, H. K., Plasma Δ9 THC concentrations and effects after oral and intravenous administration and smoking, Clin. Phamacol Ther. 28:409-416 (1980), summarized in Table 2 below. As can be seen, inhalation is the preferred route of delivery for Δ9 THC. When compared to oral delivery, inhalation provides a more rapid onset of pharmacological action and peak plasma levels. The effects achieved via inhalation are comparable to those achieved when the drug is administered intravenously, but inhalation is a much less invasive technique.

TABLE 2

Pharmacokinetics of Δ9 THC Given Orally, Intravenously or by Smoking

Onset of

% Dose in

Pharmacological

Peak Plasma

Route

Dose

Plasma

Action

Levels

References

Oral, sesame

2.5, 5, or

10 to 20%

0.5 to 1 hour

120-480 min

(PDR, 1995)

oil in gelatin

10 mg

capsules

Oral, in

20 mg

4 to 12%

120-180 min

60-90 min

(Ohlsson, et

cookies

al., 1980)

Intravenous,

5 mg

100%

10 min

3 min

(Ohlsson, et

bolus

al., 1980)

Smoking

13 mg

8 to 24%

10 min

3 min

(Ohlsson, et

(THC lost to

al., 1980)

side stream

smoke and

pyrolysis

Currently, the sources of Δ9 THC for patients who could benefit from the drug are limited. An oral form of Δ9 THC (MARINOL) is marketed as a treatment for nausea and vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade Δ9 THC is dissolved in sesame oil, encapsulated in gelatin capsules and delivered orally. However, when the drug is taken orally, the absorption is slower and more variable than when inhaled, with an onset of action between 30 minutes and 2 hours (Table 2). Drawbacks of MARINOL include its slow onset of action and extensive first-pass metabolism (Mattes, R. D. Shaw, L. M., Edling-Owens, J., Engelman, K., Elsohly, M. A., Bypassing the first-pass effect for the therapeutic use of cannabinoids, Pharmacol Biochem Behav, 44:745-747 (1993); Ohlsson, Lindgren, Whlen, Agurell, Hollister, Gillespie, Plasma delta-9-hydrocannabinol concentration and clinical effects after oral and intravenous administration and smoking, Clin Pharmacol Ther (1980), supra; PDR, 2000; Perlin, E., Smith, C. G., Nichols, A. I., Almirez, R., Flora, K. P., Cradock, J. C., Peck, C.C., Disposition and bioavailability of various formulations of tetrahydrocannabinol in the rhesus monkey, J Pharm Sci, 74:171-174 (1985)). There is also the difficulty of taking an oral medication during nausea and vomiting.

The Institute of Medicine (IOM) recently reviewed the scientific evidence for the potential of marijuana and its cannabinoid constituents to act as therapeutic agents. Joy, J., Watson Jr., S., Benson, J. E., Marijuana and Medicine: Assessing the Science Base (Washington, D.C.: National Academy Press, 1999). This report concluded that there is a potential for cannabinoid drugs, mainly Δ9 THC, for alleviation of pain, control of nausea and vomiting, and stimulation of appetite. However, they pointed out that marijuana is a “crude Δ9—THC delivery system” that delivers harmful chemicals along with the delivery of Δ9 THC, and recommended instead the development of a rapid-onset, reliable, and safe delivery Δ9 THC system. The House of Lords Select Committee on Science and Technology (Ninth Report) made similar suggestions to the British Government (House-of-Lords-Select-Committee-on-Science-and-Technology, 1998). Although the scheduling of cannabis has not been changed by the British or U.S. governments, the U.S. FDA has rescheduled MARINOL to a Schedule 3 drug, thus increasing the feasibility of developing other delivery forms of the drug.

There is no currently available pharmaceutically acceptable aerosol form of Δ9 THC. It would be advantageous to have available a form of pharmaceutical grade Δ9 THC that could be administered as an aerosol. This would provide a means for rapid uptake of the drug. Also, the potential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of pharmaceutically pure Δ9 THC could be administered in known, controlled dosages. In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of Δ9 THC. Olsen, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. ,An inhalation aerosol of Δ9-tetrahydrocannabinol. J Pharmacy and pharmacol., 28:86 (1976). However, Δ9 THC is known to deteriorate during storage, and the stability of Δ9 THC in this formulation is suspect. In addition, the ethanol content in this formulation was so high (˜23%) as to create an aerosol with droplets too large to be effectively inhaled. Dalby, R.N. and Byron, P. R., Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions, Pharm. Res. 5:36-39 (1988). The Δ9 THC CFC formulations were tested for use in treating asthma but were shown to be only moderately effective. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W., Bronchial effects of aerosolized Δ9-tetrahydrocannabinol in healthy and asthmatic subjects, Amer. Rev. of Resp. Disease. 115.:57-65 (1977); Williams, S. J., Hartley, J. P. R. and Graham, J. D. P., Bronchodilator effect of delta-9-THC administered by aerosol to asthmatic patients. Thorax. 31:720-723 (1976). Moreover, CFC propellants have since been banned so that a CFC propellant alternative would be particularly useful. It would clearly be advantageous to develop new aerosol formulations using a non-CFC propellant and having other advantageous features.

To date, much of the Δ9-THC aerosol exposure in humans concentrates on the bronchodilation effects of Δ9-THC. Tashkin et al. (1977) used a Δ9-THC MDI to deliver aerosolized Δ9-THC to healthy and asthmatic patients in an effort to assess bronchodilation as well as possible side effects due to systemic absorption. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L., Lodge, J. W., Bronchial effects of aerosolized delta-9-tetrahydrocannabinol in healthy and asthmatic subjects, Am Rev Respir Dis, 115:57-65 (1977). In healthy patients, bronchodilation was seen, as well as substantial systemic side effects (increased heart rate and subjective reports of being ‘high’) at higher doses. However, in some asthmatic patients, bronchoconstriction occurred. Tashkin et al. suggested that large particle size of the Δ9-THC aerosol may have caused the local irritant effects. Vachon et al. (1976) reported the use of a nebulized Δ9-THC micro-aerosol to achieve bronchodilation without systemic effects, however, the propylene glycol vehicle had irritant effects. Vachon, J., Robins, A., Gaensler, E. A., Airways, response to aerosolized delta-9-tetrahydrocannabinol: preliminary report, in The therapeutic potential of marijuana, eds. Cohen, S., Stillman, R.C., pp. 111-121 (New York: Plenum Medical Book Co., 1976). Williams et al. (1976) also used a low concentration of Δ9-THC for bronchodilation without systemic side effects or detectable levels of Δ9-THC in the blood. Williams, S. J., Hartley, J. P., Graham, J. D., Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients, Thorax, 6:720-723 (1976). It would clearly be advantageous to develop new aerosol formulations in which the Δ9 THC is stable, the droplets are of a size that can be effectively inhaled, and which use a non-CFC propellant.

Such objectives have been long desired but difficult to achieve, because of problems such as the difficulty of working with Δ9 THC, large dosage amounts required for Δ9 THC, and properties of Δ9 THC that make it unlike, and not interchangeable with, most other drugs. For example, Δ9 THC resembles rubber-cement, rather than a powder like most drugs, and thus presents formulation difficulties. Scientists working with THC found that they had to go to great lengths to combat its instability, based on its instability to light, oxygen, acids, bases, metal ions, etc. Thus, after the initial interest in the 1970s in THC/CFC aerosols, scientists generally settled into an acceptance of the unworkability of a THC aerosol. The initial promise of a THC aerosol according to J. L. Olsen, J. W. Lodge, B. J. Shapiro and D. P. Tashkin (1975) never materialized, and in the past few decades it has been conventionally thought that THC is not suited for aerosol-dispensing, and especially not for MDI-dispensing.

Thus, a pharmaceutically effective THC aerosol that overcomes the above-mentioned limitations of the prior art, especially an MDI-dispensible aerosol would be much desired.

SUMMARY OF THE INVENTION

The present inventors have now discovered, surprisingly, that THC dissolves well in HFA and that an aerosol-dispensable THC/HFA, pharmaceutical composition—i.e., a sufficiently stable composition and at the high doses which are required for THC—may be formulated. The present invention exploits these surprising discoveries. It is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a non-CFC propellant and a pharmaceutically effective concentration of Δ9 THC, and Δ9 THC derivatives (e.g., cannabinoids such as Δ8-tetrahydrocannabinol, 11-hydroxy Δ9-tetrahydrocannabinol, cannabinol, cannabidol, nabilone, levonantradol, (−)-HU-210, Win 55212-2, Anandamide, Methandamide, CP 55940, O-1057, SR141716A, etc.). More particularly, it is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a hydrofluoroalkane propellant (for example, HFA 227 or HFA 134a) and Δ9 THC. The propellant is present in the range of approximately 78 to 100% by weight, and more particularly the propellant is present in the range of approximately 85 to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the Δ9 THC in the propellant but is not required. If a solvent is used, preferably less than 20% by weight will be required, and most preferably less than 15% by weight will be required. The pharmaceutically effective concentration of Δ9 THC is preferably in the range of 0.05 to 10% by weight, and most preferably in the range of 0.1 to 6% by weight. The pharmaceutical composition of the present invention can be used to treat a variety of medical conditions including nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, anorexia associated with cancer chemotherapy, epilepsy, glaucoma, bronchial asthma, mood disorders, migraine headaches.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Δ9 THC MDI characterization summary before and after storage at 40° C. and 82% relative humidity (RH).

FIGS. 4A-D are graphs showing the effect of pretreatment with SR 141716A on the behavioral effects of inhaled Δ9-THC according to the invention for mice.

FIG. 5 is a graph of % MPE versus SR 141716A dose, showing the dose-response relationship of SR 141716A in antagonizing the antinociceptive effects following exposure to aerosolized Δ9-THC according to the invention.

FIG. 6A is the chemical structure for HFA 134a; FIG. 6B is the chemical structure for HFA 227.

When the propellant is a hydrofluoroalkane, it has been discovered that the propellant may be used with or without a solvent such as ethanol. Higher percentages of solvent generally allow higher levels of dissolution of Δ9 THC. However, higher percentages of solvent also cause droplet size to increase. In preferred embodiments of the invention, the range of propellant compositions, as shown in Table 3, may be from 100% propellant and 0% solvent to 85% propellant and 15% solvent. Within this range of percentages, pharmaceutically useful concentrations of Δ9 THC can be achieved and droplet size is still small enough (<5.8 um) to provide excellent aerosol delivery of the drug. While these ratios reflect preferred embodiments of the invention, it will be recognized by those of skill in the art that the exact ratio of propellant to solvent (e.g. ethanol) may vary according to the desired final concentration of Δ9 THC and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the Δ9 THC may be used in the practice of this invention, and this will generally be in the range of from 100 to 80% propellant and 0 to 20% solvent. It is expected that a wide variety of solvents, such as ethanol, propanol, propylene glycol, glycerol, polyethylene glycol, etc. may be used in the preparation of formulations contemplated by this invention.

Those skilled in the art also will recognize that the “respirable dose” (or mass of Δ9 THC in particles with aerodynamic diameters small enough to be delivered to and absorbed by the lungs) (FIG. 1) may be increased by choosing MDI spray nozzles of different design and smaller orifice diameters. Respirable doses may also be increased by extending the mouthpiece of the MDI in such a way as to create an integral or separate aerosol spacer or reservoir attached to the mouthpiece of the MDI. This promotes an increase in droplet evaporation and hence in the percentage of the dose in smaller “respirable” particles or droplets. Generally, the optimal size of a respirable droplet is less than 10 micrometers (μm) in size. The size of a droplet in an aerosol may be measured by cascade impaction and is characterized by the mass median aerodynamic diameter (MMAD) (the value for which 50% of the particles are larger or smaller). Using THC aerosols according to the present invention, an MMAD of 2.5 μm or better may be provided.

TABLE 3

Apparent Solubility of Δ9 THC in Ethanol/HFA Propellant Blends

Mass (g) of

Mass (g) of

Apparent

Δ9 THC in

Formulation

Solubility

Formulation

Sample

Sampled

Mean (±SD)

Comments

Δ9 THC in

0.000240

0.1071

0.224% w/w

Excess Δ9 THC

100% HFA

(±0.063)

added to propellant

134a

blend (in pressurized

MDI). Solubility

sample removed

using puff absorber

n = 5

Δ9 THC in 5%

0.00144

0.0914

1.585% w/w

As above

Ethanol/95%

(±0.321)

HFA 134a

Δ9 THC in

0.00363

0.1036

3.511 % w/w

As above

10%

(±0.249)

Ethanol/90%

HPA 134a

Δ9 THC in

0.00536

0.1098

4.883% w/w

As above

15%

(±0.224)

Ethanol/85%

HFA 134a

Δ9 THC in

0.00021

0.1451

0.147% w/w

As above

100% HFA 227

(±0.008)

Δ9 THC in 5%

0.00134

0.0979

1.339% w/w

As above

Ethanol/95%

(±0.169)

HFA 227

Δ9 THC in

0.00454

0.1267

3.240% w/w

As above

10%

(±0.161)

Ethanol/90%

HFA 227

Δ9 THC in

0.00623

0.1062

5.940% w/w

As above

15%

(±0.191)

Ethanol/85%

HFA 227

A distinct advantage of the present formulations is that, surprisingly, the use of surface active agents or “surfactants” as valve lubricants and solubilizers is not necessary. This is in contrast to the invention of Purewal and Greenleaf (European Patent 0,372,777 (Riker Laboratories), Medicinal aerosol formulations) which provides HFA 134a/ethanol mixtures to produce stable formulations of pharmaceuticals in the presence of lipophilic surface active agents. Lipophilic surface active agents are incorporated in that invention in order to suspend undissolved material and to ensure adequate valve lubrication of the MDI. Without adequate valve lubrication, the useful life of the MDI and its ability to deliver an accurate dose of drug are severely attenuated. However, probably due to the inherent lubricity of the formulations of the present invention, the use of such surface active agents is unnecessary. This simplifies the composition and thus is an advantage with respect to cost and the elimination of potentially deleterious interactions between components of the formulations and the agents.

A major consideration in the formulation of any drug is its stability. Δ9 THC is known to deteriorate upon storage so that the effective concentration decreases and the purity is vitiated. The stability of the formulations of the present invention were tested according to accelerated storage testing protocols. The results are given in FIG. 1 and Tables 4A and 4B. The formulations of the present invention were shown to be stable with respect to the release of aerosolized Δ9 THC in reproducible doses following accelerated storage testing. Apparently, the containment of Δ9 THC in solution in the non-aqueous formulations of the present invention is excellent with respect to chemical degration, making possible the construction of a multidose inhaler with a good shelf life prognosis.

Further, lipophilic materials like Δ9 THC are generally known to partition into the elastomers of the valves in MDI formulations. (Δ9 THC is highly lipophilic as reflected in its octanol:water partition coefficient of 6000:1). Over time, this partitioning results in a decrease in the emitted or delivered dose of a liophilic drug. Thus, this phenomenon also decreases the useful shelf-life of such preparations. However, the data presented in FIG. 1 and Table 4 show that this is not the case with the formulations of the present invention. The emitted or delivered doses were constant over the time period tested. This may be due to the somewhat surprising preference of Δ9 THC for the formulation itself; rather than for the valve elastomers.

The final concentration of Δ9 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the Δ9 THC. Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of Δ9 THC to be dissolved. For example, in preferred embodiments of the invention, the apparent solubility of Δ9 THC ranged from 0.147% w/w to 5.94%. w/w as the propellant composition varied from 100% HFA 227 to 85% HFA 227 and 15% ethanol. Thus, the dose of Δ9 THC in a given metered volume may be selected by changing the formulation.

Further, as stated above, the “fine particle dose” or “respirable dose” of a drug dispensed with an MDI is a function of the spray nozzle diameter. In FIG. 1 and Tables 4A and 4B, the spray nozzle diameter is 0.4 mm. The “fine particle dose” or “respirable dose” of the formulations of the present invention was shown to be unaffected by storage.

The Δ9 THC of the present invention is pharmaceutically pure. That is, its form is the nonionized resinous drug substance (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-1-ol. Although its preferred embodiment in this invention is not a salt or ester, it will be readily understood by those of skill in the art that other appropriate forms of Δ9 THC may be synthesized (e.g. esters and salts such as those described in, for example, U.S. Pat. No. 5,847,128 and PCT WO 01/03690, hereby incorporated in their entirety by reference) and thus used in the practice of this invention.

The desired final concentration of Δ9 THC in a patient's serum will vary from patient to patient depending on, for example, the nature and severity of the condition being treated, and the patient's overall condition, weight, gender and response to the drug, etc. But the desired range will generally be 10-100 ng/ml at 15 minutes following inhalation. The level of Δ9 THC in a patient's serum can be readily and reliably monitored by gas chromatography/mass spectrophotometry (GC/MS).

The exact treatment protocol to be used may vary from patient to patient depending on the circumstances. For example, in a preferred embodiment of the invention, a patient receiving chemotherapy may have one dose of Δ9 THC prescribed via inhalation, to be administered 15 minutes before chemotherapy and 4-8 times daily following chemotherapy. In another preferred embodiment, a patient suffering from anorexia associated with AIDS wasting syndrome may have Δ9 THC by inhalation prescribed 3-5 times daily, 30 minutes before each meal or snack. In other preferred embodiments, a patient suffering form cancer pain, or spasticity related to either multiple sclerosis or spinal cord injury may have Δ9 THC by inhalation prescribed 3-6 times daily. Those skilled in the art will readily recognize that the treatment protocol may be crafted so as to address the particular needs of each individual patient on a case by case basis.

Δ9 THC may be used alone or in combination with other medications. Those skilled in the art will readily recognize that, for example, in the case of AIDS wasting syndrome, the patient will likely also be taking drugs that combat the AIDS virus. Similarly, those skilled in the art will readily recognize that patients receiving chemotherapy for cancer may also receive other antiemetics, and cancer patients seeking to relieve pain are likely to receive opioids as well as nonsteroidal anti-inflammatory agents. The containers for the formulations of the instant invention may be any that are suitable for the efficacious delivery of aerosol inhalants. Several containers and their method of usage are known to those of skill in the art. For example, MDIs can be used with various dose metering chambers, various plastic actuators and mouthpieces, and various aerosol holding chambers (e.g. spacer and reservoir devices), so that appropriate doses of Δ9 THC reach and deposit in the lung and are thereafter absorbed into the bloodstream. In addition, a lock mechanism such as that shown in U.S. Pat. No. 5,284,133 to Bums and Marshak, which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of Δ9 THC. FIG. 2 provides a generalized drawing of an MDI containing the composition of this invention and provides the advantage of delivering metered quantities of Δ9 THC on a repetitive basis. The MDI includes a container 100 for holding the composition and a valve delivery mechanism 102 for delivery of aerosolized Δ9 THC.

IN VIVO EXPERIMENTATION

A Δ9 THC MDI was formulated and the physical properties of the aerosolized drug characterized. The mass of drug metered by the metering valve was determined following a single actuation (metered dose). The mass of drug delivered (emitted dose) was determined. The mass of particles with an aerodynamic diameter less than 4.7 μm was determined.

Male ICR mice, weighing approximately 30 g, obtained from Harlan Laboratories (Indianapolis, Ind.) were provided a light cycle of approximately 6 a.m. to 6 p.m., and the temperature remained approximately 23° C. The mice were placed in the lab and allowed to accommodate to the surroundings the evening prior to testing. Animals were allowed food (Harlan Teklab, Madison, Wis.) and water ad libitum.

Appearance, metered dose reproducibility, emitted dose and particle size distribution of the Δ9 THC MDI were investigated, before and after storage in an environment maintained at 40° C. and 82% relative humidity for a 28 day period. The mass of drug metered by the metering valve (metered dose, n=10) was determined by collecting single actuations directly from the valve in a puff absorber, using the methods of Byron, 1994. The mass of drug delivered (emitted dose, n=10) was investigated at 28.3 1 min−1 using the USP Dosage Sampling Apparatus (USP, Physical Tests and Determinations, <601>, Aerosols, metered-dose inhalers, and dry powder inhalers, in United States Pharmacopeia, (USP 24), pp. 1895-1912 (Philadelphia, VA: National Publishing, 2000). Particle size analysis of Δ9-THC MDI was determined by drawing the samples through an Andersen Cascade Impactor (Andersen Samplers Inc., Atlanta, Ga.) at a volumetric flow rate of 28.3 liter/minute following United States Pharmacopeial guidelines (n=5; USP, 2000). The fine particle dose (n=5), defined as the mass of particles with an aerodynamic diameter less than 4.7 μm, was then determined.

THC was analyzed by LC-UV detection at 280 nm using a 75:25 acetonitrile: 1% acetic acid mobile phase for Δ9-THC detection. A standard reverse phase C18 column was used. A calibration curve was constructed for each assay based on linear regression of the Δ9-THC standard peak areas.

The exposure chamber was a modified, inverted, 1-liter separation funnel, housed under a fume hood, which allowed four mice to be simultaneously exposed to the aerosol. Air was drawn through the chamber at a rate of approximately 60 ml/minute and filtered through glass wool (Corning Inc., Corning, N.Y.) and charcoal traps (SKC Inc., Eighty Four, Pa.) upon exiting the exposure chamber. Each actuation of Δ9-THC or vehicle was delivered once per 5 s and the entire exposure period was 10 min. Mice were exposed to 20, 40 or 60 actuations of aerosolized Δ9-THC or 60 actuations of vehicle.

Mice were placed in separate clear chambers (16.5 cm×25.5 cm×11.5 cm high) and assessed for hypomotility using a Digiscan Animal Activity Monitor (Omnitech Electronics Inc., Columbus, Ohio) in which the total number of photocell-light beam interruptions was counted. Antinociception was assessed in the tail-flick test (D'Amour, F. E., Smith, D. L., A method for determining loss of pain sensation, J Pharm Exp Ther, 72:74-79 (1941)) with heat intensity adjusted to give baseline latencies ranging from 2.0-4.0 seconds. A cut-off time of 10 seconds was used to limit tissue damage. Percent maximum possible effect (%MPE) was determined according to the following formula:

%MPE=[(test latency-baseline latency)/(cut-off-baseline latency)]*100

A ring-test procedure was used to assess catalepsy. The percent of time during a five minute observation period that mice remained motionless, except for movements related to respiration, while stationed on a 5.7 cm diameter ring stand 23 cm above the laboratory bench, was assessed. Body temperature was assessed by inserting a thermometer probe (Traceable Digital, Control Co., Friendswood, Tex.) 2.5 cm into the rectum. Subjects were assessed for baseline tail-flick latency and rectal temperature prior to drug or vehicle administration. In the antagonism studies, mice were given an i.p. injection of SR 141716A or vehicle five-minutes prior to inhalation exposure of aerosols from 60 actuations of either a vehicle or a Δ9-THC MDI. Locomotor activity, tail-flick latency, catalepsy, and hypothermia were assessed 5, 20, 40, and 60 minutes, respectively, after aerosol exposure. An additional group of animals was given an i.v. injection of Δ9-THC (0.3, 1, 3, or 10 mg/kg) or vehicle into a lateral tail vein and assessed in the tail-flick test 20 minutes later. All injections were given in a volume of 0.1 ml per 10 g animal weight.

Blood and brain levels of Δ9-THC were determined as follows. Extraction and LC-MS quantification of Δ9-THC from whole blood and brain tissue were modified from Lichtman, A. H., Poklis, J. L., Wilson, D. M., Martin, B. R., The pharmacological activity of inhalation exposure to marijuana smoke in mice, Drug Alc Depend, 63:107-116 (2001). Particularly, THC and 2H3-THC were extracted from brain material which contains a high degree of lipids. Acetonitrile was added to the pelletized solids and stored in a freezer overnight to separate the acetonitrile layer (which contained THC/2H3-THC) from the aqueous layers. The following day the acetonitrile layer was removed. In the Lichtman et al., study, 2 ml of 9:1 NaOH was added and the sample was vortexed. Four ml of 9:1 hexane:ethyl acetate was added and the sample was vortexed and spun at 30 rpm for 30 minutes. The vials were then centrifuged at 4,000 rpm at 30 rpm for 10 minutes. The organic layer was removed and evaporated. Upon drying, a derivatizing agent was added and the sample was vortexed, and each sample analyzed by GC/MS. In the present experimentation, the acetonitrile was instead evaporated to dryness under nitrogen. The material was then resolubilized in 0.1 ml methanol. LC-MS identification was used to quantify Δ9-THC/2H3-THC in blood and brain matrices. In the present experimentation, calibration standards were prepared from blank mouse whole blood and homogenized brain (2:1, water:brain, v:w). Fifty ng of 2H3-THC (Radian Corporation, Austin, Tex.) was added to the blood sample, brain homogenate, and calibrators as an internal standard. Following an equilibration period, 2.5 ml of cold acetonitrile (HPLC grade, Fisher Scientific, Raleigh, N.C.) was added drop-wise while vortexing. The samples were then centrifuged (Precision Vari-Hi-Speed Centricone, Precision Scientific Co., Chicago, Ill.) at 2500 rpm for 15 minutes to pelletize solids, then stored in the freezer (−20° C.) overnight, allowing the acetonitrile layer to separate from the aqueous layers. The acetonitrile layer was then removed and evaporated to dryness under nitrogen. The Δ9-THC/2H3-THC was then resolubilized in 0.1 ml methanol (HPLC grade, Fisher Scientific).

LC-MS identification was used for quantification of Δ9-THC and 2H3-THC in blood and brain matrices using an 85:15 methanol: 1% glacial acetic acid (0.1% formic acid) mobile phase. A guard column was used inline with the standard reverse phase C18 column. The mass spectrometer was run in APCI+mode. Ions analyzed in single ion monitoring mode were 315 for Δ9-THC and 318 for 2H3-THC. A calibration curve was constructed for each assay based on linear regression using the peak-area ratios of Δ9-THC to 2H3-THC of the extracted calibration samples.

The statistical analysis of the data was as follows. Data are represented by means±standard error (s.e.). Statistical analysis of the data was performed using Student t-tests (for the physiochemical comparisons of the aerosol), or ANOVA (for pharmacological studies), with significance set at p<0.05. Post hoc tests for significant ANOVAs included either Dunnett's test or Tukey/Kramer post-hoc analysis. All ED50 values were determined using least squares linear regression analysis and calculation of 95% confidence limits (Bliss, C. I., Statistics in Biology (New York: McGraw-Hill, 1967) and were based on the number of actuations of the MDI (i.e., 1 mg/actuation). The Emax for depression of locomotor activity was calculated by double reciprocal plot. The Emax value for percent immobility was assigned the mean from the group that was exposed to 60 mg Δ9-THC. The Emax values for antinociception and hypothermia were 100% MPE and 6° C. respectively. The ED50 of SR 141716A in antagonizing the antinociceptive effects of Δ9-THC was determined through least squares linear regression analysis and calculation of 95% confidence limits (Bliss, 1967). A sample size of 6-8 mice was used in each group.

Results: THC MDI Physiochemical Characteristics

As shown in Table 5 below, the physiochemical characteristics of the aerosolized Δ9-THC were unaffected following storage at 40° C. with 82% relative humidity for 28 days. The mass of drug metered by the metering valve following a single actuation was reproducible and unaffected by the accelerated stability storage (p>0.1). There was little variance in the emitted dose and no significant effect of storage (p>0.1). The fine particle dose represented 23.0±0.8% before and 23.6±0.8% after accelerated stability testing of the emitted dose and exhibited no deterioration in Δ9-THC content (p>0.1).

FIGS. 4A-D show the effect of pretreatment with the specific CD1 receptor antagonist, SR 141716A on the behavioral effects of inhaled Δ9-THC. Two-way ANOVA revealed that SR 141716A (10 mg/kg) significantly blocked Δ9-THC-induced hypomotility (F(1,28)=7.4, p<0.05), antinociception (F(1,28)=25.2, p<0.05), catalepsy (F(1,28)=7.4, p<0.05), and hypothermia (F(1,28)=28.9, p<0.05). The groups given a vehicle pretreatment and exposed to the Δ9-THC aerosol differed from all other groups for each measure (Tukey test, p<0.05).

The dose-response relationship of SR 141716A in antagonizing the antinociceptive effects following exposure to 60 mg of aerosolized Δ9-THC is shown in FIG. 5. SR 141716A significantly blocked the antinociception, F(5,30)=21.6, p<0.05, with an AD50 (95%C.L.) of 0.8 (0.7-1.1 mg/kg.

Table 6 shows the blood and brain Δ9-THC concentrations, 20 mm after either inhalation exposure to Δ9-THC aerosol or intraveneous injection of Δ9-THC. Increasing the amount of drug delivered resulted in increasing concentrations of Δ9-THC in both matrices. The blood levels of Δ9-THC following aerosol exposure 20, 40, or 60 mg delivered increased in a dose dependent fashion and were comparable to the blood levels produced by intravenous injection of 3 and 10 mg/kg Δ9-THC. Brain levels of Δ9-THC following those exposures were similar to that of 1 and 3 mg/kg intravenous injection of Δ9-THC. There was dissociation in Δ9-THC blood and brain concentrations between the inhalation and intravenous routes of administration, an interesting result because other drugs such as methamphetamine, heroin and phencyclidine have been observed to lead to similar brain:blood plasma ratios between the two routes of administration. For the present experimentation, whereas brain levels were 200-300% higher than blood levels following i.v. injection of Δ9-THC, the brain levels of Δ9-THC were roughly equivalent to the blood levels of Δ9-THC following inhalation.

Antinociceptive effect and blood and brain concentrations of Δ9-THC 20 min after treatment

route of

% MPE

ng Δ9-THC/g blood

ng Δ9-THC/g brain

administration

THC dose

(mean ± S.E.)

(mean ± S.E.)

(mean ± S.E.)

inhalation

20 actuations

37 ± 11*

409 ± 86

340 ± 36

40 actuations

58 ± 14*

788 ± 273

791 ± 94

60 actuations

78 ± 11*

1132 ± 240

890 ± 151

intravenous

1 mg/kg

31 ± 8

102 ± 6

307 ± 28

3 mg/kg

70 ± 14

365 ± 39

854 ± 42

10 mg/kg

67 ± 11

1324 ± 38

3307 ± 190

*From FIG. 3B

Comparison of MDI antinociceptive potency with blood and brain concentrations of Δ9-THC resulted in a high correlation (r2=0.997 and r2=0.889 for blood and brain, respectively). Additionally, comparison of blood and brain levels of Δ9-THC at antinociceptive EC50 doses for inhalation and i.v. injection of Δ9-THC as well as comparison of potency ratios between the two routes of administration revealed no significant differences in the different matrices (Table 7).

TABLE 7

Comparison of Δ9-THC blood

and brain concentrations at antinociceptive ED50 doses

Route of

Blood

Brain

Administration

ED50 (95% C.L.)

ED50 (95% C.L.)

ED50 (95% C.L.)

inhalation

30 (20-44)

591 (403-866)*

506 (333-769)*

actuations

intravenous

2.4 (1.4-4.2)

230 (102-521)

604 (270-1350)

mg/kg

*Potency ratios (95% C.L.) in blood, 1.8 (0.5-4.2), and in brain, 0.6 (0.2-1.5), were not significantly different

Unlike parenteral methods of delivery in which a known amount of drug is injected, determining the absorbed dose of an inhaled drug is difficult to quantify. Although a large mass of drug was actuated into the inhalation chamber, the majority of drug mass is lost because it either deposits on the exposure apparatus or escapes with exhausted air out of the apparatus. Additionally, physiological properties, such as tidal volume and respiratory rate, influence drug inhalation. Finally, because mice are obligate nasal breathers, many particles do not reach the lungs. Therefore, for the above experimentation, dose was indirectly assessed by comparing the concentration of Δ9-THC in whole blood and brain after inhalation and i.v. routes of adminstration. For both routes of administration, the concentrations of drug increased in both matrices with increasing doses. Inhalation exposure of each respective dose of aerosolized Δ9-THC resulted in equivalent concentrations of the parent compound in blood and brain. On the other hand, i.v. administration resulted in Δ9-THC brain levels that were approximately two to three fold higher than those found in blood. The EC50 values for inhalation exposure and i.v. injection in the above experimentation were not significantly different in either matrix. Consequently, exposure to the Δ9-THC aerosol produced dose-dependent increases of Δ9-THC in blood and brain levels, and the levels necessary to produce cannabinoid behavioral effects were similar to i.v. injection.

In applying the results of the above experimentation on mice to other animals, it will be taken into account that mice are obligate nose-breathers with an extensive nasal infra-architecture, such that substantial nasal deposition may have hindered alveoli deposition. Schlesinger (1985) reported upper respiratory tract deposition of particle sizes between 2-3 μm ranged from 20-40%. Schlesinger, R. B., Comparative deposition of inhaled aerosols in experimental animals and humans: a review, J Toxicol Environ Health, 15:197-214 (1985). Using empirical modeling, Asgharian et al. (1995) calculated that less than 15% of particles with a mass median aerodynamic diameter of 2-3 μm could reach the alveolar regions of rats compared to a 40% value in humans, and this percentage would be expected to be even lower in mice because of the smaller respiratory tract and general anatomical differences between rats and mice. Asgharian, B., Wood, R., Schlesinger, R. B., Empirical modeling of particle deposition in the alveolar region of the lungs: A basis for interspecies extrapolation, Fund Appl Toxicol, 27, 232-238 (1995). Consequently, a considerable amount of the exposed dose is likely to have been deposited in the upper respiratory tract of the mice. In addition, such impacted particles could be moved to the throat, via ciliary action, and swallowed, resulting in gastrointestinal absorption. However, such absorption would not be expected to be as rapid as alveolar absorption. Hence, this delayed absorption might act to maintain Δ9-THC blood and brain levels for a prolonged period of time. Despite-the extensive filtering done by mice, the fine particle dose generated by the MDI (i.e., 0.22 mg per actuation) was sufficient to result in the rapid elicitation of pharmacological behavior suggesting that the behavioral effects were due to absorption in either the lungs or the upper respiratory tract and not due to gastrointestinal absorption. Nonetheless, nasal filtering is of little concern in humans and the fact that locomotor depression occurred within 5 minutes of exposure and antinociception occurred at 20 minutes is consistent with the notion that a sufficient amount of the aerosol reached the lungs.

The results of Tables 5-7 and FIGS. 3A-5 are particularly significant because of the difficulties of exploiting properties of, and effectively delivering, Δ9-THC. For example, cannabinoid activity in mice has been reported following exposure to marijuana smoke; however, placebo smoke mimicked marijuana in hypothermia and locomotor inhibition assays. Lichtman et al., 2001. Moreover, in the Lichtman et al. study, SR 141716A only effectively antagonized the antinociceptive response, raising concerns that exposure to the other chemicals in burned marijuana besides Δ9-THC, as well as possible effects of a hypoxic state, were of consequence there. These other chemicals may have unwanted and unexpected interactions with other drugs. Thus, delivering Δ9-THC without all the other chemicals of marijuana is highly advantageous. However, such Δ9-THC delivery has not been easily provided. The behavioral effects of a Δ9-THC aerosol generated by a nebulizer have been reported, A. H. Lichtman, J. Peart, J. L. Poklis, D. T. Bridgen, R. Z. Razdan, D. M. Wilson, A. Poklis, Y. Meng, P. R. Byron, B. R. Martin, “Pharmacological evaluation of aerosolized cannabinoids in mice,” Eur. J. Pharmacol. 399:141-149 (2000). While this method for exposing mice to a Δ9-THC aerosol removed the confounding influence of smoke, the only cannabinoid behavior observed was a moderate degree of antinociception. Although separation of the potentially therapeutic effects, such as antinociception, from the other pharmacological effects of Δ9-THC is a desirable goal, the modest cannabinoid effect was attributed to the relatively low blood levels of Δ9-THC. A 10-minute exposure to the nebulized aerosol resulted in a drug blood concentration of approximately 100 ng Δ9-THC/ml blood, whereas the Δ9-THC blood levels of mice following a 10 minute exposure to 20 actuations of the MDI aerosol was around 400 ng/g blood. (Table 8.) Another problem with using the nebulizer to deliver aerosolized Δ9-THC is the vehicle for dissolution of Δ9-THC, with some surfactants (such as Emulphor) not having FDA approval for inhalation exposure in humans.

TABLE 8

Δ9-THC blood levels in mice

Δ9-THC blood level

Administration

(ng Δ9-THC/ml blood)

Nebulized aerosol*

100

MDI aerosol** (20 actuations)

400

*Emulphor as the surfactant

**Ethanol cosolvent; HFA 134a propellant

Other advantages of Δ9-THC delivery according to the present invention also are seen. The present invention delivers a systemic dose of Δ9-THC via the lungs. The development of a Δ9-THC MDI, which leads to-a rapid onset of action, consistent blood levels, and by-passing the first-pass metabolism in the liver, suggests the viability of the Δ9-THC aerosol as a replacement for oral Δ9-THC.

In sum, the experimentation discussed above with regard to Tables 5-7 and FIGS. 3A-5 show, inter alia, that a Δ9-THC MDI was formulated that can be used to provide a systemic dose of Δ9-THC via the lungs, and that a Δ9 THC MDI is capable of producing the full constellation of cannabinoid effects in mice. Physiochemical characteristics of the aerosol were assessed before and after accelerated stability testing. Following this characterization, mice were exposed to the aerosol and evaluated for pharmacological effects indicative of cannabinoid activity, including hypomotility, antinociception, catalepsy, and hypothermia. The CB1 receptor antagonist SR 141716A was used to determine whether the pharmacological effects were mediated by the cannabinoid receptor. The fine particle does of Δ9 THC was 0.22±0.03 mg (mean±S.D.) or 25% of the emitted dose. In addition, the physiochemical properties of the aerosol were unaffected by accelerated stability testing. A 10-minute exposure to aerosolized Δ9 THC elicited hypomotility, antinociception, catalepsy, and hypothermia. Additionally, Δ9 THC concentrations in blood and brain at the antinociceptive ED50 dose were similar for both inhalation and intravenous routes of administration. Finally, pretreatment with 10 mg/kg (i.p.) of SR 141716A significantly antagonized all of the Δ9 THC-induced effects. These results indicate that an MDI is a viable method to deliver a systemic dose of Δ9 THC that elicits a full spectrum of cannabinoid pharmacological effects in mice that is mediated via a CB1 receptor mechanism of action.

The experimental findings set forth herein suggest that an aerosolized form of Δ9-THC for medicinal use may be provided. Dosages for mice have been provided, and typically human doses are about 100 times lower than mouse doses on a mg/kg basis. The demonstration that a Δ9-THC aerosol, generated by a MDI, is relatively stable and produces systemic pharmacological effects in mice has clinical applications in the treatment of many disorders, including pain management as well as the indications for orally-available Δ9-THC. The availability of a highly reproducible Δ9-THC aerosol, without exposure to potentially harmful chemicals and carcinogens present in marijuana smoke, is particularly advantageous for the treatment of human patients.

While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims.

The effect of orally rectally administered 9-tetrahydrocannabinol on spasticity: A pilot study with 2 patients, Institute of Pharmacy, University of Bern; International Journal of Clinical Pharmacology and Therapeutics, vol. 34 No. 10-1996 (446-452).